Ayvakit
avapritinib
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The Applicant evaluated the toxicity of avapritinib in GLP-compliant repeated-dose toxicity studies in rats and dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats received up to 30 mg/kg/day of oral avapritinib, once per day, for 3 months, resulting in mean exposure levels (AUC) up to 6 times the AUC of 15400 ng.h/mL in humans at the 300 mg daily dose.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“choroid plexus edema in the brain occurred in dogs at doses greater than or equal to 7.5 mg/kg/day (approximately 4.7, 1 or 0.4 times the human exposure based on AUC at the 25 mg, 200 mg or 300 mg dose, respectively), but were not observed in a 9-month study at 5 mg/kg/day.”
Pivotal GLP studies
28-day and 3-month oral studies in rats and dogs
“Local tolerance was assessed by reviewing the digestive track changes in the GLP-compliant 28-day and 3-month toxicology studies in rats and dogs.”
Route in tox
Oral (gavage)
“3-month oral (gavage) toxicity and toxicokinetic study in Sprague Dawley rats”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; positive in vitro chromosome aberration; negative rat bone marrow micronucleus; overall non-genotoxic
“Avapritinib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Avapritinib was positive in the in vitro chromosome aberration test in human peripheral blood lymphocytes but negative in the in vivo rat bone marrow micronucleus test, and overall non-genotoxic.”
Carcinogenicity
6-month transgenic mouse study: negative up to 20 mg/kg/day
“Avapritinib was not mutagenic in a 6-month transgenic mouse study up to the highest dose evaluated at 20 mg/kg/day.”
Reproductive & developmental
Rat EFD: reduced fetal weight, post-implantation loss, visceral and skeletal malformations at >=10 mg/kg/day (~2.7x human AUC)
“Daily oral administration of avapritinib to pregnant rats resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses ≥ 10 mg/kg/day (a dose resulting in exposures approximately 2.7 times the exposure based on AUC at the 300 mg human dose).”
Safety pharmacology
No pulmonary or cardiovascular effects up to 45 mg/kg; hERG IC50 2.4 μM (1.5x human free Cmax)
“There were no avapritinib-related adverse effects on pulmonary function or the cardiovascular system at single doses up to 45 mg/kg. Avapritinib blocked hERG channel potential with an IC50 of 2.4 μM; however, this IC50 is 1.5 times the free Cmax in humans at the 300 mg dose.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Ayvakit don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x (EMA assessment report, p. 50)
NOAEL / key findings
Dogs: brain hemorrhage and choroid plexus edema at >=0.4x human exposure; rat convulsions at >=8x
“Repeat dose studies in dogs indicated haemorrhage and choroid plexus oedema in the brain at ≥ 0.4 times the human exposure at the clinical dose of 300 mg once daily. Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid system effects (spleen, thymus) did not reverse
“All effects were reversible or reversing with three notable exceptions: effects in the lymphoid system (spleen and thymus), brain and the gonads.”
Biodistribution & persistence
Pigmented rats: uveal tract and skin levels 2-330-fold higher than in albino rats, with slower elimination
“The concentration of [14C]-avapritinib-derived radioactivity in the uveal tract and skin of pigmented Long Evans rats was eliminated more slowly and was approximately 2 to 330-fold higher than in these tissues in nonpigmented rats.”
Modality-specific risk
CNS toxicity: convulsions in rats, possibly via Nav1.2 inhibition, at >=8x clinical exposure
“Rats manifested convulsions, which was potentially secondary to inhibition of Nav 1.2 at systemic exposures ≥8-fold higher than the exposure in patients at the clinical dose of 300 mg once daily.”